Abstract
Although cell invasion is a necessary early step in cancer metastasis, its regulation is not well understood. We have previously shown, in human prostate cancer, that transforming growth factor β (TGFβ)-mediated increases in cell invasion are dependent upon activation of the serine/threonine kinase, p38 MAP kinase. In the current study, downstream effectors of p38 MAP kinase were sought by first screening for proteins phosphorylated after TGFβ treatment, only in the absence of chemical inhibitors of p38 MAP kinase. This led us to investigate mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), a known substrate of p38 MAP kinase, as well as heat-shock protein 27 (HSP27), a known substrate of MAPKAPK2, in both PC3 and PC3-M human prostate cells. After transient transfection, wild-type MAPKAPK2 and HSP27 both increased TGFβ-mediated matrix metalloproteinase type 2 (MMP-2) activity, as well as cell invasion, which in turn was inhibited by SB203580, an inhibitor of p38 MAP kinase. Conversely, dominant-negative MAPKAPK2 blocked phosphorylation of HSP27, whereas dominant-negative MAPKAPK2 or mutant, non-phosphorylateable, HSP27 each blocked TGFβ-mediated increases in MMP-2, as well as cell invasion. Similarly, knock down of MAPKAPK2, HSP27 or both together, by siRNA, also blocked TGFβ-mediated cell invasion. This study demonstrates that both MAPKAPK2 and HSP27 are necessary for TGFβ-mediated increases in MMP-2 and cell invasion in human prostate cancer.
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Acknowledgements
This work was funded by the following grants to Raymond C Bergan: Specialized Program of Research Excellence (SPORE) Grant CA90386, from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and by a merit review award from the Veterans Administration. We wish to thank Professor Matthias Gaestel (Institute of Biochemistry, Medical School, Hannover, Germany) for kindly providing us plasmids for wild-type of MAPKAPK2, pcDNA3mycMK2WT, dominant-negative kinase-inactive mutant, pcDNA3mycMK2K76R, and constitutively active mutant, pcDNA3mycMK2T205E317E. We also wish to thank Professor Rainer R Benndorf (Departments of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA) for kindly providing us plasmids for the wild type of HSP27, pcDNA3.1-HSP27 WT and non-phosphorylateable mutant of HSP27, pcDNA3.1-HSP27 3G.
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Xu, L., Chen, S. & Bergan, R. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 25, 2987–2998 (2006). https://doi.org/10.1038/sj.onc.1209337
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DOI: https://doi.org/10.1038/sj.onc.1209337
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